Transition metal-catalyzed cross-coupling reactions of organometallics are key transformations in organic synthesis. Their broad spectrum of applications ranges from the synthesis of small molecular units to the construction of organic materials and complex natural products. Besides Kumada-Corriu-coupling, the Suzuki-Miyaura-, and the Negishi-cross-coupling reactions are of great importance in various chemical and pharmaceutical manufacturing applications.
Organozinc reagents used in Negishi-couplings can be prepared in a convenient and cheap way by direct oxidative addition of zinc metal into organic halides. Various functionalized aryl, heteroaryl and benzylic zinc reagents are accessible via such cross-coupling reactions in good yields. Cross-coupling reactions with zinc organometallics can be performed under mild conditions and in good yields with a broad spectrum of electrophiles. Consequently, organozinc reagents are of considerable interest for industrial applications. They can be stored as solutions in THF under inert gas atmosphere for several weeks without significant loss of activity.
However, it would be advantageous in terms of storage as well as transportation and manipulation on an industrial scale to use organozincs as solid materials. So far, zinc reagents of the composition RZnX, RZnX.LiCl and RZnX.MgCl2.LiCl (R=aryl, heteroaryl, benzyl, alkyl and X=Cl, Br, I) have only been obtained as highly viscous oils after the evaporation of the solvent and have therefore not been available as solids.
There is also a desire to increase the selectivity of cross-coupling reactions to allow sensitive functional groups such as ester, aldehyde, nitrile and nitro to be present in the electrophiles.
The invention disclosed herein addresses this and other shortcomings in metalated reagents suitable for use in commercial-scale cross-coupling reactions as further described and disclosed below.